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DOI: 10.1177/0269881108100322 2009; 23; 401 originally published online Jan 22, 2009; J Psychopharmacol

S Hood, G ONeil and G Hulse psychological profiles

The role of flumazenil in the treatment of benzodiazepine dependence: physiological and

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The role of flumazenil in the treatmentof benzodiazepine dependence:physiological and psychologicalprofiles

S Hood School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia.G ONeil Australian Medical Procedures Research Foundation, Perth, Australia.G Hulse School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia.

Abstract

Two-related studies are presented here, detailing our early experience withbenzodiazepine-dependent patients treated with a four-day flumazenilinfusion using a novel delivery technique. Patients with long-termbenzodiazepine dependence who attended the Australian MedicalProcedures Research Foundation (AMPRF, Perth, Australia) for treatmentwere recruited for these studies. Self-reported psychological and physicalsymptoms, as well as objective vital signs data were collected at intervalsbefore, during and 2 weeks postinfusion. Study A is a case series withcardiovascular measures; study B is an open trial that tracks thepsychological profiles of 13 subjects. Withdrawal symptoms were tracked,however, the nature and severity of these symptoms differed between

patients. No major complications or discomfort prompting study dropoutwas observed. Significant benzodiazepine abstinence occurred with thisflumazenil infusion method despite high levels of initial dependence,comorbid substance use and comorbid psychiatric illness. Low-doseflumazenil infusion appears to be a safe and effective treatment resultingin withdrawal symptoms of lesser severity than any other cessation methodcurrently available. Recommendations for future research are discussed.

Key wordsbenzodiazepine withdrawal; case series; comorbidity; flumazenil; infusion;naturalistic; safety

Introduction

The clinical introduction of the benzodiazepine chlordiazepox-ide in 1960 was a landmark in modern psychopharmacology.Benzodiazepines were hailed as successors to the barbiturates,the addictive potential and side effects of which were causingconsternation, and which themselves had in the 1930s replacedopium as anxiolytics. Soon after their introduction, reports ofbenzodiazepine dependency emerged (Hollister, et al., 1961),supported by later studies in animals (Petursson and Lader,1981b) and humans (Covi, et al., 1973; Lader, 1983). Between15 and 44% of chronic benzodiazepine users become dependentand experience moderate to severe withdrawal symptoms uponcessation (Ashton, 1991; de las, et al., 2000), including emer-gent anxiety and depressive symptoms (Ashton, 1991; Peturs-son and Lader, 1981a). Issues of benzodiazepine dependence,rebound anxiety, discontinuation syndromes, social impactand novel therapies remain topical (Chouinard, 2004; Dong,et al., 2007; Heberlein, et al., 2008) and relevant.

Management of benzodiazepine dependence usuallyinvolves either progressive withdrawal or abrupt discontinua-

tion, with switching to a longer half-life benzodiazepine oradjunctive medications having a more limited evidence base(Ashton, 2005; Denis, et al., 2006). Tapering and psychologicalsupport may minimise withdrawal distress (which is linked torelapse (Bergman, et al., 1989)); however, the duration of suchtreatment may be months to years (Ashton, 1991; Hulse, et al.,2002).

Benzodiazepines bind to a modulatory site on the gamma-aminobutyric acid, subtype A (GABA-A) receptor complex,enhancing (agonism) GABA-A activity. The imidobenzodiaze-pine flumazenil (Ro 15-1788) is an agent commonly used in thetreatment of benzodiazepine overdose (Thomson, et al., 2006;Weinbroum, et al., 1996). At low doses (

1997). Nevertheless, multiple bolus infusions of flumazenil canreduce distress experienced by patients treated for benzodiaze-pine dependence (Gerra, et al., 2002; Saxon, et al., 1997), how-ever, its very short half-life and low oral bioavailability limitits use in clinical settings.

In an effort to address these limitations, our group and col-leagues at Go Medical Industries Pty Ltd (Perth, Australia)have developed a mobile portable balloon infusion pump todeliver flumazenil in a continuous manner (ONeil BalloonInfuser, ID: SBI-100, http://www.gomedical.com.au/products/infusion_balloon.php).

In this report, we present two-related observational studiesof our flumazenil infusion procedure in the treatment of benzo-diazepine dependence. Study A is a case series wherein wedetail the course of three markedly benzodiazepine-dependentpatients treated with this novel delivery system, with particularfocus on cardiovascular measures. Study B examines the psy-chological profiles before, during and immediately after the flu-mazenil procedure in 13 benzodiazepine-dependent patients.

Methods and materials

Subjects

Patients attending the Australian Medical Procedures ResearchFoundation (AMPRF) Subiaco Clinic site in Perth, Australiafor flumazenil treatment of long-term benzodiazepine depen-dence and who were willing and able to provide writteninformed consent were eligible for study. The subjectsdescribed here are a representative sample of the severity andcomorbidity of patients presenting to this clinic. Dr ONeil, theinventor of this clinical medication delivery system, providesclinical oversight at this centre and administers the flumazenilinfusions. The flumazenil infusion protocol is similar to thatreported by Gerra, et al. (2002) (Quaglio, et al, 2005) with2 mg/day of flumazenil being infused for up to 96 h. Congruentwith Gerra, et al. (2002), patients received rapidly tapereddoses of oxazepam (60 mg on day 1, 30 mg on day 2, 15 mgon day 3, no benzodiazepines on day 4). Infusions, at a rateof 2 mg/24 h, were commenced in the detoxification clinic andthe patient observed for the first 4 h. Following this, the patientwas allowed home accompanied by a reliable relative elseaccommodation was provided in a residential house adjoiningthe clinic. Patients were monitored again at 72 h and 2-weekintervals.

In study A, respiratory rate and blood pressure recordingswere monitored. Additionally, physical and psychologicalsymptoms taken from the Ashton Benzodiazepine WithdrawalSymptom Rating Scale (ABWSRS) (Ashton, 1991) wererecorded. Symptoms were assumed to relate to withdrawal ifthey were reported on at least two separate points of follow-up and were not present preinfusion.

In study B, subjects were regularly monitored during theflumazenil infusion procedure. Immediately prior to com-mencing the flumazenil infusion, subjects were assessed by an

experienced clinician (GO), drug use history recorded, and thefollowing rating scales administered by lay persons trainedin their use: Mini-International Neuropsychiatric Interview(MINI v5) (Sheehan, et al., 1998), Spielberger State-TraitAnxiety Inventory (SSAI) (Spielberger, et al., 1983), Profile ofMood States Questionnaire (POMS) (McNair, et al., 1988) anda series of Visual Analogue Scales (VASs) (Bond and Lader,1974; Fresco, et al., 2001). Ten of the VAS questionnairesrelated to physical symptoms of anxiety and withdrawal(shaky, headache, nausea, sweaty, thirsty, abdominal discom-fort, restless, tense, dizzy, blushing) and ten to cognitive symp-toms (anxious, depressed, detached, embarrassed, worried,concentration, secure, frustrated, hallucinations, craving ben-zodiazepines). During the flumazenil infusion phase and twiceweekly for 2 weeks afterwards, subjects were asked to repeatthe VAS, SSAI and POMS questionnaires, in addition to areturn to drug use survey.

The studies were conducted according to the ethical princi-ple of the Declaration of Helsinki and were approved by theHuman Research Ethics Committee of the University ofWestern Australia.

Statistical analysis

As these studies are naturalistic and observational, onlydescriptive statistics are presented here. Data from study Bwere interrogated post hoc using SPSS for Windows version15 (SPSS Inc. Chicago, Illinois, USA), however, we are awareof the dangers of over-interpreting analyses of observationaldatasets (Assmann, et al., 2000) and report only the mostrobust findings here.

VAS scores were reversed for Secure and Concentration(i.e., to Insecure and Impaired concentration) so that higherscores for all VAS measures relate to high impairment. Stan-dardised scores of VAS-total, VAS-cognitive and VAS-physical, as well as VAS-craving benzodiazepines wereanalysed.

Results

Study A

Case 1 This 32-year-old man had initially received a fluma-zenil infusion 8 months previously as an inpatient. Insomniawas the predominant recalled emergent symptom. Before thishe had been taking 1000 mg of diazepam each day. There wasa significant history of polysubstance misuse, with a daily habitthat also included 150 mg methadone, 1 g heroin, 3 g ofamphetamines and UK 2000 of crack cocaine.

At the time of the current infusion, he had been using mari-juana, dexamphetamine, cocaine and amphetamines. His dailybenzodiazepine intake consisted of diazepam 75 mg, oxazepam150 mg, nitrazepam 20 mg and temazepam 40 mg. The patientsuffered from chronic insomnia and self-medicated with

402 Flumazenil in the treatment of benzodiazepine dependence


benzodiazepines. He expressed concern over the potential forhis insomnia to return over the withdrawal period.

This patient experienced few adverse effects and toleratedflumazenil extremely well. There were few withdrawal symp-toms, with only moderate to severe sore eyes and mild to severethirst noted. Interestingly, the patient reported an improvementin his insomnia whilst undergoing flumazenil infusion.

Some symptoms were present preinfusion but disappearedonce infusion was commenced. These included mild fatigue,moderate restlessness, muscle twitches and limb stiffness,severe obsessions, teeth and jaw pain, dry mouth and mildataxia.

The patient reported only one episode of each of poor mem-ory and concentration, irritability, tingling and numbness,severe urinary frequency, mildly itchy skin, increased appetite,influenza-like symptoms, stuffy nose and irritability. Thesewere not thought to represent withdrawal symptoms as theywere reported just once over the follow-up period.

The majority of symptoms on our checklist were not presenton any day of follow-up. Interestingly, although cravings werepresent on most days both preinfusion and during follow-up,only on day 1 were the cravings for benzodiazepines. At othertimes, cravings for marijuana and/or amphetamines were expe-rienced, consistent with the history of polysubstance abuseimmediately before infusion.

Vital signs on the whole remained within normal range andare graphed in Figure 1. At one stage, slight tachypnoea wasobserved (respiratory rate 24).

This patient remained abstinent from benzodiazepines andother drugs listed above for the following 2-year period, atwhich time he returned to his European country of origin.

Case 2 This 37-year-old woman presented seeked help forbenzodiazepine dependence, anxiety and depressive symptoms.Relevant medical history includes scoliosis and associatedchronic back pain and chronic alcohol dependence. She wasinitially prescribed alprazolam at age 15 as a treatment forpanic attacks, becoming dependent on benzodiazepines there-after. She had tried a number of antidepressants, antipsychoticand mood stabilising medications in the past with little benefit.A private psychiatrist had recently diagnosed adult AttentionDeficit Hyperactivity Disorder (ADHD), and the patient des-cribed a significant improvement in her ability to concentratewith dexamphetamine therapy.

Her medications at time of presentation were dexampheta-mine 30 mg, paroxetine 40 mg, quetiepine 400 mg, diazepam3550 mg and alprazolam 20 mg daily.

The patients infusion was ceased after one day due to ablockage in the delivery line. The infusion was recommencedon the following day (Day 2). On day 4 of the infusion, thecannula site became painful, swollen and inflamed, resultingin presentation to the emergency department. A diagnosis ofvenous thrombosis was made and the infusion was ceased forthe second time, and a clinical decision made not torecommence.

The withdrawal syndrome in this patient was characterisedby mild to moderate headache, ataxia, hyperventilation, stuffynose, influenza-like symptoms, sore eyes, panic attacks, weaklegs, decreased appetite, flushing and sweating; and mild tosevere symptoms of restlessness, tingling and numbness,tremor, muscle twitches, insomnia and nightmares. Mild limb,back, teeth and jaw pain was reported on the majority of daysof follow-up, as were moderate diarrhoea and severe light-headedness and dizziness.

Solitary episodes each of irritability, limb stiffness, blurredvision, tinnitus, nausea, abdominal pain, dysphagia and palpi-tations were reported with severity varying from mild to severe.No other symptoms were reported.

Vital signs were predominantly within normal range, partic-ularly heart rate and respiratory rate (see Figure 1). Slighthypertension was observed in the early days of infusion.

The patient remained benzodiazepine free at 2-week follow-up and was very positive about her clinical progress. By3 months, she had returned to occasional alcohol and benzodi-azepine use; this remained at that level when last reviewed1 year postinfusion.

Case 3 A 28-year-old woman with a history of polysubstanceabuse presented for assistance with cessation of her benzodiaz-epine habit. Her previous intake consisted of diazepam 250 mg,temazepam 20 mg and oxazepam 1500 mg/day. Immediatelybefore commencing the infusion, she had managed to reducethis to 360 mg oxazepam and 90 mg diazepam/day. There wasalso a history of alcohol dependency treated with naltrexoneimplants and opiate dependency treated with buprenorphine.

Few symptoms were experienced until 9 h into the infusion,at which stage the patient developed notable back and abdom-inal muscular pain. The subject was reviewed at a local hospitalemergency department, and the infusion was ceased an hourlater. The patient was discharged from the emergency depart-ment and the infusion recommenced the following morning.

Emergent symptoms were mild to moderate blurred vision,speech difficulty and metallic taste; mild to severe anxiety,fatigue, increased appetite and hypersensitivity to light; moder-ate to severe restlessness, limb and back pain and headache.Mild dizziness and light-headedness were reported on all daysof follow-up. One episode of each of visual perceptual distur-bance, phobias, paranoid ideation, weak legs, urinary fre-quency and nausea occurred over the follow-up period. Thesesymptoms were judged not to be clinically significant.

Vital signs are displayed in Figure 1. Heart rate was consis-tently elevated, though this was also true of the baseline mea-surement. Blood pressure and respiratory rate both remainedwithin normal limits throughout the study. The subject self-reported ongoing drug use, primarily marijuana and dexam-phetamines, during the infusion period.

At 2-week follow-up, the patient remained abstinent andoptimistic of no further relapse. At one month postinfusion,she was using oxazepam on some days. Subsequently she waslost to follow-up.

Flumazenil in the treatment of benzodiazepine dependence 403


Study B

As anticipated, there were multiple missing data episodes inthis observational and naturalistic study of a largely itinerantsubstance-withdrawing cohort. Manual data screening showed13 subjects with sufficient data integrity, who are the basis ofthis report, of whom seven were women. Post-hoc analysesshowed no trends or significant effects of sex, age or psychiatricdiagnostic group. Baseline data are summarized in Table 1.

The MINI diagnostic interview was recorded in these sub-jects, and for clarity, the results are collapsed into letter diag-nostic groups in Table 2. All subjects showed psychiatriccomorbidity including a depressive disorder and 91% qualifiedfor an anxiety disorder diagnosis. We interrogated the data setfor effect of a present or past diagnosis of panic disorder, due toour prior findings in panic disorder patients given Intravenous(i.v.) flumazenil as described above, but there was no evidenceof any trend or impact upon the other outcome measures.

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Polysubstance use was markedly reduced for up to 2 weekspostinfusion (see Figure 2), and no illicit benzodiazepine usewas seen. VASs of cognitive, physical and craving symptomsas well as POMS Total Mood Impairment and SSAI-rated anx-iety scores remained essentially stable throughout the infusion and

postinfusion phases of this treatment (Figures 3 and 4), with atrend for improvement in symptoms in all these measures by theend of infusion (+72 h).

Discussion

Clinical trials, especially trials used to support registration ofnew medicines by regulatory bodies, are frequently criticisedfor the artificial, highly selected, noncomorbid nature of thesample populations (Sacristan, et al., 1998). This case series,however, describes the effects of a novel flumazenil infusionsystem in benzodiazepine-dependent subjects who are typicalof patients seen in routine clinical settings. They have highlevels of substance use, polydrug habits, ongoing drug use dur-ing treatment, and variable motivation and treatmentadherence.

In study A, we found that continuous flumazenil infusionenabled three subjects with severe benzodiazepine dependenceto successfully discontinue benzodiazepine use. These subjectsremained abstinent for very significant periods up to 2 yearsin this series. The severity of withdrawal syndrome varied inthis series. Case 1 experienced a highly bearable withdrawalsyndrome with almost no symptoms. Case 3 experienced amoderate withdrawal syndrome, whereas case 2 experienced arelatively severe withdrawal syndrome. However, all patientsstated that their symptoms were tolerable and none attemptedto cease the infusion at any stage.

Subjects in study B showed high levels of psychiatric illness.Depressive and anxiety comorbidity was usual, in addition tovery significant polysubstance use as shown in Figure 2. Base-line anxiety was in the moderate clinical range according toSSAI, and the POMS scores are congruent with markedimpairment. From the normal values listed in the POMS man-ual (McNair, et al., 1988), the POMS Total Mood Disturbancemean of 98 seen in this study is higher than that of normalcollege students (43), outpatient males (65.5) and females(81.5) and is similar to that seen in cocaine-dependent personswho drop out of inpatient treatment (97.2) (Wilkins, et al.,2005).

Figure 2 compares self-reported substance use in the4 weeks prior to the flumazenil infusion procedure with thefinal recorded use postinfusion. Although we accept that thereis a potential for subjects returning to substance use to under-report it in this context and the supportive rehabilitation envi-ronment likely to have a beneficial effect beyond flumazenilsaction, the results are still striking and are congruent with thecase histories detailed in study A. Additionally, the staff at thisclinic have long-term therapeutic relationships with many ofthese clients, increasing the likelihood of candid disclosure.Tracking of psychological measures (Figure 4) show stabilityin these measures over time, that is, craving, anxiety, moodsymptoms did not increase over the infusion and postinfusionperiods. A trend for improvement on all these measures at+72 h mark of the infusion may suggest that an even longerflumazenil infusion period could have additional benefits.

Table 1 Study B baseline

Parameter Value(s)

Sex 7 female/6 maleAge 31 (11.3) yearsRecent drug use

Intravenous benzodiazepines (past 4 weeks) 18%Opiates (past 7 days) 30%Amphetamines (past 7 days) 23%

Spielberger State-Trait Anxiety (range 2080)State 52 (16.9)Trait 55 (6.6)

Profile of Mood States (POMS) ScoreTotal Mood Disturbance 98 (45.7)Tension Anxiety 24 (10.5)Depression Dejection 29 (15.9)Anger Hostility 22 (12.7)Vigour Activity 9 (6.3)Fatigue Inertia 16 (7.8)Confusion Bewilderment 14 (6.1)Friendliness 16 (7.5)

Values are expressed as counts or as mean (standard deviation).

Table 2 MINI diagnoses by letter category

Diagnostic group %

A Depression 75B Dysthymia 75C Suicidality 91D Mania 60

Depression or Mania 90Depression or Dysthymia 100

E Panic 75F Agoraphobia 27G Social anxiety disorder 41H OCD 41I PTSD 66J Alcohol dependence/abuse 40K Substance dependence/abuse 100L Psychosis 41M/N Eating disorder 8O GAD 75

Anxiety disorder 91R/S/T/U Somatoform 22

No comorbidity 0

OCD, Obsessive Compulsive Disorder; PTSD, Post Traumatic Stress Disorder;GAD, Generalised Anxiety Disorder.



How does flumazenil work as a treatment of benzodiaze-pine dependence? There are several possible explanations. Oneis that it resets the benzodiazepine receptor set point that isshifted in the inverse agonist direction by chronic use of benzo-diazepines (Nutt and Costello, 1988). Second, it may attenuatethe urge to take benzodiazepines due to a partial agonist actionwithout overt precipitation of drug effects (Gerra, et al., 2002).Third, it can upregulate GABA-A receptors (Jazvinscak, et al.,2008) and facilitate coupling of the GABA-A and benzo-diazepine (BZD) receptor complexes, potentially reversing thedownregulation/uncoupling that occurs with long-term benzo-diazepine misuse (Ali and Olsen, 2001). Long-term (48 h) expo-sure to flumazenil upregulates GABA-A receptors in vitro(Jazvinscak, et al., 2008).

The use of flumazenil in doses of only 80 g/h represents aninfusion level that is likely to only reach a small percentage ofreceptors at any one time congruent with the gradualimprovement that occurs the longer the infusion is run.

The ability of low-dose bolus i.v. flumazenil as used here totreat benzodiazepine dependence needs to be reconciled withthe experience of one of the authors (SH) (Bell, et al., 2002)and by others (Harrison-Read, et al., 1996) that (high dose)i.v. flumazenil is a powerful anxiety-provoking challenge. How-ever, flumazenil infusions are not usually anxiogenic in nonan-xious controls, patients with other anxiety disorders or evenpatients with remitted panic disorder.

This is an observational case series conducted in a routineclinical treatment setting and has the limitations common to

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Figure 2 Study B substance use (i) in 4 weeks before infusion and (ii) last record post infusion.



such data sets including a small sample size, the use of nonre-search clinicians (and training medical students) for data col-lection, confounding uncontrolled comorbid substance use/licit medication coprescription/and possible comorbid (undiag-nosed) psychiatric illness. We were not able to identify any sys-tematic biases in the subjects use of self-report measures, asthere was no incentive for over-reporting symptoms (such asgaining access to treatments) in this clinical context.

In our experience, flumazenil is a relatively safe drug ofchoice for the treatment of severe benzodiazepine dependence.

In an estimated 260 infusions carried out using this method byourselves and colleagues in Perth and Melbourne, we have seenonly one seizure (causing a fall and limb fracture). As it has anexcellent teratogenic profile (Jurand and Martin, 1994;Schlappi, et al., 1988) and does not antagonize the centraldepressant effects of (commonly concomitant) barbiturates,ethanol, ketamine, valproate or morphine (Bonetti, et al.,1982), it is especially suited to routine clinical populations.Treatment-emergent withdrawal symptoms were not seen inour sample. This procedure may also prove to be of help in

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some patients with anxiety disorders and especially in patientswith withdrawal symptoms that continue for weeks or monthsfollowing benzodiazepine withdrawal.

Intravenous flumazenil infusions in the method describedhere needs further development before becoming a routine treat-ment of benzodiazepine dependence. Refinement of novel deliv-ery systems such as depot preparations may assist in its use,safety and long-term impact of this novel therapeutic tool is val-

idated in the treatment of patients with severe benzodiazepinedependence, who currently have few alternative solutions.

AcknowledgementsChristina Bertilone, Jennifer Hill and Simon Kavanagh for their workin collecting data for study A as part of a 4th year medical studentresearch option supervised by GH & GO.

Angeline Ong for data collection and entry.

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A/Prof Hans Stampfer for 24 h circadian rhythm recordings andanalysis.

Staff and clients of the Australian Medical Procedures ResearchFoundation (AMPRF) Clinic (Fresh Start) in Perth, Australia.

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